ORIGINAL ARTICLE

Chloral Hydrate, Chloral Hydrate - Promethazineand Chloral Hydrate -Hydroxyzine Efficacyin Electroencephalography Sedation

Razieh Fallah & Ali Alaei & Sedighah Akhavan Karbasi &Ahmad Shajari

Received: 27 March 2013 /Accepted: 30 October 2013# Dr. K C Chaudhuri Foundation 2014

AbstractObjective To compare efficacy and safety of chloral hydrate(CH), chloral hydrate and promethazine (CH + P) and chloralhydrate and hydroxyzine (CH +H) in electroencephalography(EEG) sedation.Methods In a parallel single-blinded randomized clinical trial,ninety 1–7 y-old uncooperative kids who were referred toPediatric Neurology Clinic of Shahid Sadoughi University,Yazd, Iran from April through August 2012, were randomlyassigned to receive 40 mg/kg of chloral hydrate or 40 mg/kgof chloral hydrate and 1 mg/kg of promethazine or 40 mg/kgof chloral hydrate and 2 mg/kg of hydroxyzine. The primaryendpoint was efficacy in sufficient sedation (obtaining fourRamsay sedation score) and successful completion of EEG.Secondary endpoint was clinical adverse events.Results Thirty nine girls (43.3 %) and 51 boys (56.7 %) withmean age of 3.34±1.47 y were assessed. Sufficient sedationand completion of EEG were achieved in 70 % (N =21) ofchloral hydrate group, in 83.3% (N =25) of CH+H group andin 96.7 % (N =29) of CH + P group (p =0.02). Mild clinicaladverse events including vomiting [16.7 % (N =5) in CH,6.7 % (N =2) in CH + P, 6.7 % (N =2) in CH + H], agitation

in 3.3 % of CH + P (N =1) group and mild transient hypoten-sion in 3.3 % of CH + H (N =1) group occurred. Safety ofthese three sedation regimens was not statistically significantdifferent (p =0.14).Conclusions Combination of chloral hydrate—antihistaminescan be used as the most effective and safe sedation regimen indrug induced sleep electroencephalography of kids.

Keywords Chloral hydrate . Promethazine . Hydroxyzine .

Sedation . Electroencephalography

Introduction

Up to 5 % of general population experiences one nonfebrileseizure during their lifetime and electroencephalography(EEG) is indicated in patients with first unprovoked seizure[1].

During EEG recording, the patient should be immobile andin almost no case, sedation is really necessary. But in notnaturally sleeping, uncooperative children, sleep should beinduced by sedation regimens [2].

Many sedative drugs have been used in children EEG seda-tion and the drugs must be of no or minimal effect on thebackground and epileptic discharges of the EEG [2–4].Midazolam may induce scalp EEG signal changes andwidespread augmentation of sigma-oscillations [5].Dexmedetomidine sedation elicits the EEG pattern similar toStage II of sleep with modest increases in theta, alpha, and betaactivity and it has no effect on EEG epileptiform activity inchildren [6]. But, dexmedetomidine is expensive and hardlyavailable in many developing countries such as Iran.

One of the most frequently administered sedative drugs inchildren is chloral hydrate (CH) that can be used in dosage of40–100 mg/kg [7]. But, it has not been effective in some of thechildren, even in maximum dose and its long action duration

R. Fallah : S. Akhavan KarbasiDepartment of Pediatrics, Growth Disorders of Children ResearchCenter, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

A. AlaeiAli-ebn-Abitaleb School of Medicine,Islamic Azad University, Yazd Branch, Yazd, Iran

A. ShajariDepartment of Pediatrics, Ali-ebn-Abitaleb School of Medicine,Islamic Azad University, Yazd Branch, Yazd, Iran

S. Akhavan Karbasi (*)Shahid Sadoughi Hospital, Ave - Sina Blvd,Shahid Ghandi Blvd, Yazd, Islamic Republic of Irane-mail: sakarbasi@yahoo.com

Indian J PediatrDOI 10.1007/s12098-013-1298-y

is concerning, airway obstruction and suppression of respira-tory effort with intra and post procedural oxygen desaturation,consistency in sedation effects and its carcinogenicity poten-tiality, especially at high doses [7–9], and it may also beaccompanied by post-discharge side effects in doses of 70–100 mg/kg [10].

Melatonin as a useful oral natural-sleep agent can modulatethe circadian rhythm of sleep; it does not change the quality ofrecording EEG in epileptic children [11] and after chloral hy-drate, melatonin is next commonly used drug for sedation forEEG.

Chloral hydrate in dosage of 40 mg/kg is safer and itscombination with antihistamines might decrease chloral hydratedosage [8, 12]. Combination of chloral hydrate and hydroxyzinehas been used for sedation of children in dental procedures andit can decrease dosage need of chloral hydrate and also causeimprovement in safer sleeping of the patient and decrease therisk of chloral hydrate related nausea and vomiting [12].

Promethazine is an inexpensive and easily feasible anti-emetic and antisialagogue agent which nowadays is primarilyused as a sedative agent [13, 14].

The aim of present research was to compare effectivenessand safety of chloral hydrate alone in the minimum dosage,combination of chloral hydrate - promethazine (CH + P) andcombination of chloral hydrate - hydroxyzine (CH + H) inchildren electroencephalography sedation.

Material and Methods

A parallel single-blinded randomized clinical trial was con-ducted on children who were referred to electroencephalogra-phy room of Pediatric Neurology Clinic of Shahid SadoughiUniversity, Yazd, Iran from April through August 2012.

To determine a 20% difference in efficacy between the threegroups, with type one error (alpha) of 0.05 and 80 % powerbased on a study done in the past in authors’ department [4],sample size was estimated as 30 children in each group.

Eligible participants included children aged 1–7 y, thosewho were guided to electroencephalography room forrecoding of EEG and those who did not naturally sleep andwere uncooperative with EEG device. These children were inclass 1 (healthy persons) or 2 (a patient with mild systemicdisorders: mild asthma, controlled diabetes mellitus, etc.) ofAmerican Society of Anesthesiology [15].

Those with gastritis, severe systemic disorders, serioussystemic reaction, head trauma and taking a sedative drugwithin 2 d, were excluded.

Simple randomization of the study was computer generatedby random numbers and allocation ratio was 1:1 for the threegroups.

A researcher who was not involved in the trial, did therandomisation and blinding. Data gatherers, endpoint

assessors and data analysts were all allocation blinded. But,patients and allocated EEG staff to the intervention groupwere aware of the allocated arm. A pharmacist prepared thedrugs and the drugs were given in a suspension of 1 cc/kg. Forsedative identification prevention, medicine bottles were cod-ed; code was known only to the EEG staff unit.

EEG staff delivered the drug and primary and secondaryendpoints were assessed by the study general physician that hadno information of the sedation regimens group assignment.

Ninety consecutive children who were referred for EEGand were uncooperative with the EEG setup and requiredsedation were randomly assigned to three groups to receivechloral hydrate in dosage of 40 mg/kg (Group I) or 40 mg/kgof chloral hydrate and 1 mg/kg of promethazine (Group II) or40 mg/kg of chloral hydrate and 2 mg/kg of hydroxyzine(Group III).

The drugs were given orally in the three groups and beforethe patients entered the electroencephalography room.

Heart rate, respiratory rate, blood pressure, and saturationof oxygen during 60 min after sedative drug administration,were monitored continuously and all vital signs were mea-sured every 15 min by the general physician of research.

Obtaining four Ramsay sedation score [16] was consideredas sufficient sedation.

The primary endpoint was efficacy in sufficient sedationand successful EEG recording. Secondary endpoints wereclinical adverse events, severe side effects (hypotension, hyp-oxia and cyanosis, serious vomiting, refractory irritability andagitation, apnea, laryngospasm, and bradycardia), time fromdrug taking to sufficient sedation, caretakers’ satisfaction on aLikert scale (5 for completely satisfied, 4 for satisfied, 3 forpartially satisfied, 2 for partially unsatisfied and 1 forcompletely unsatisfied) and total stay time in the EEG room.

Assisted ventilation, Respiratory depression, oxygen satu-ration of less than 90 %, or a 25 % or greater decrease inbefore sedative drug taking mean arterial blood pressure, werethought of as severe adverse events.

Not achieving sufficient sedation (child awakened ormoved, interfered with EEG recording, inadequate sedationand need for other sedative drugs) and procedure failure due tosevere side effects, were considered as abortion of sedationregimen.

A pediatric neurologist assessed the developmental statusof the children by Denver Developmental screening test-II [4].

The data were analyzed using SPSS: 17 statistical software.Recorded data were assessed for normal distribution using theShapiro Wilk test and qualitative variables data analysis wasdone by Chi-square test. Comparison of mean values wasdone by ANOVA test and as a significant result was obtained,the Tukey test was applied for post hoc pair wise comparisons.

Kaplan–Meier survival analysis was used to calculate prob-ability of adequate sedation during the observation period. Pvalues of less than 0.05 were taken as statistically significant.

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Informed consent was taken from patients’ parents beforeadministration of the drugs and the Ethics Committee of Ali-ebn-Abitaleb School of Medicine, Islamic Azad University,Yazd Branch, Yazd, Iran has approved this clinical trial.

The registration number of the research in clinical trials ofIran is IRCT201204262639N8. Meanwhile, the researchersgot no support from the drugs company.

Results

Four hundred fifty six children underwent EEG during thestudy period and amongst them, 90 consecutive uncooperativechildren with EEG setup including 39 girls (43.3 %) and 51boys (56.7 %) with age of 3.34±1.47 y were investigated. Nolosses to follow-up or exclusions were seen.

After application of Shapiro Wilk test, the data had normaldistribution.

Table 1 presents comparison of characteristics of childrenin different groups and shows that mean of age and mean ofweight, sex distribution, developmental status and age groupof children were not statistically significantly different in thethree groups.

Sufficient sedation and successful EEG recording wereachieved in 21 children (70 %) in chloral hydrate (95 % con-fidence interval: 0.54–0.86), in 29 children (96.7 %) in chloralhydrate-promethazine (95 % CI: 0.9–1) and in 25 children(83.3 %) in chloral hydrate-hydroxyzine (95 % CI: 0.67–0.97) groups, respectively. Statistical analysis showed thatcombination of CH + P or CH + H was more effective thansole chloral hydrate in sedation induction (p value=0.02).

All the children who were not sedated required re-sedationwith other sedation regimens.

Probability of being adequately sedated vs. time after tak-ing the drugs by Kaplan–Meier plots is shown in Fig. 1 andindicates that Ramsay sedation score of four was obtained inall children who achieved adequate sedation 40 min aftertaking the drugs.

Abnormal epileptiform discharges on EEG were seen in63.4% (N =19) of chloral hydrate group, in 66.7% (N =20) ofCH + H group and in 56.7 % (N =17) of CH + P group (pvalue=0.7) and yield of epileptic discharge detection was notstatistically different in the three groups.

The only drug effect on background rhythm of EEG wasgeneralized fast beta activity followed by slow delta activity intemporal regions. The occurrence of fast background rhythmwas not statistically different in three groups [12 children(40 %) in chloral hydrae group, 11 children (36.7 %) inCH + H group and 10 children (33.3 %) in CH + P group;p value=0.86].

Table 2 compares means of some variables and shows thatCH + H group sooner obtained four Ramsay sedation scorethan CH + P and alone chloral hydrate groups. In groups ofchloral hydrate and antihistamine combination (hydroxyzineor promethazine), as compared to sole chloral hydrate group,EEG recording completion was done in shorter time after thedrug taking and the parents were more satisfied by waitingless in the EEG unit. The table shows that the effect ofCH + H is more than CH + P. In CH + H group, Ramsaysedation score of four was sooner obtained, recording ofEEG was completed in shortest time after taking the drug andthe parents waited less in the EEG unit and were moresatisfied.

None of children had autistic feature. But, 48 childrenin all three groups were mentally retarded and adequatesedation was achieved in 39 children (81 %). Comparison ofsuccess in EEG recording in three groups based on thedevelopmental status is shown in Table 3 which indi-cates that efficacy of three sedation regimens was not signif-icantly different in children with and without developmentaldelay.

No life-threatening and severe side effects were witnessedin the three groups.

Clinical side effects such as vomiting [16.7 % (N =5) inCH, 6.7 % (N =2) in CH + P, 6.7 % (N =2) in CH + H],agitation in 3.3 % of CH + P (N =1) group and mild transient

Table 1 Comparison of some characteristics of children in the three groups

Data Chloral hydrate Chloral hydrate andpromethazine

Chloral hydrate andhydroxyzine

P value

Age in years (mean ± SD)a 3.29±1.64 3.63±1.41 3.11±1.36 0.4

Weight in kg (mean ± SD)a 13.01±4.01 13.38±3.01 12.43±3.33 0.5

Sexb Female (%) 13 (43.3) 15 (50) 11 (36.6) 0.6Male (%) 17 (56.7) 15 (50) 19 (63.4)

Developmental statusb Normal (%) 15 (50) 16 (53.3) 11 (36.6) 0.4Delay (%) 15 (50) 14 (46.7) 19 (63.4)

Age groupb <2 y (%) 8 (26.7) 6 (20) 5 (16.7) 0.6≥2 y (%) 22 (73.3) 24 (80) 25 (83.3)

a Statistical test used ANOVAb Statistical test used Chi-square test

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hypotension in 3.3 % of CH + H (N =1) group were seen.Safety of these three sedation regimens was not differentsignificantly (p =0.14).

Discussion

Many sedation regimens have been used for children sedationinduction in different procedures. In this randomized clinicaltrial, adequate sedation and completion of EEGwere achieved

in 70% of chloral hydrate group, in 83.3 % of chloral hydrate-hydroxyzine group and in 96.7 % of chloral hydrate-promethazine group and the result showed that a combinationof 40 mg/kg chloral hydrate and antihistamines was moreeffective than sole chloral hydrate in sleep induction forEEG recording in children. On the other hand, yield of epi-leptic discharge detection and effect on EEG backgroundwerenot different in these three sedation regimens which is inagreement to Britton et al. study, that yield of sleep-specificepileptic abnormalities detection was not statistically different

Fig. 1 Probability of beingadequately sedated vs. time aftertaking of the drugs by Kaplan–Meier plots

Table 2 Comparison of mean of some variables in the three groups

Groups Chloral hydrate Chloral hydrateand promethazine

Chloral hydrateand hydroxyzine

P value

Data

Acquired Ramsay sedation score 4.53±1.63 5.03±1.09 4.81±1.42 0.4

Time from drug taking to achievingadequate sedation (in min)

23.81±11.28 20.86±7.44 15.68±6.01 CH, CH + P 0.22

CH, CH + H 0.001

CH + P, CH + H 0.02

Time after taking the drug tocompleting EEG recording (in min)

39.05±13.84 32.93±8.91 27.76±7. 77 CH, CH + P 0.04

CH, CH + H 0.001

CH + P, CH + H 0.06

Caregiver’s satisfaction scale 3.27±1.38 3.91±1.06 4.11±1.23 CH, CH + P 0.02

CH, CH + H 0.01

CH + P, CH + H 0.41

Total stay time in EEG unit (in min) 58.93±16.45 49.91±11.53 45.17±13.45 CH, CH + P 0.01

CH, CH + H 0.001

CH + P, CH + H 0.19

CH Chloral hydrate; CH + P Chloral hydrate and promethazine; CH + H Chloral hydrate and hydroxyzine

The statistical test used: ANOVA for comparing on mean values and Tukey test was applied for post hoc pair wise comparisons

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in patients receiving or not receiving chloral hydrate duringroutine EEG [17].

In an another study in from authors’ department, successfulcompletion of EEG was done in 96.7 % of children whoreceived 70 mg/kg chloral hydrate [4].

In Ashrafi et al. study in Tehran, Iran, chloral hydrate indosage of 50 mg/kg was effective in recording sleep EEG of96.6 % children who aged 1 mo to 6 y. But, yield of epilep-tiform discharges in melatonin group was higher than inchloral hydrate group (53 % vs. 46 % and P =0.005) [3]. Inanother Ashrafi et al. study, yield of epileptic discharge detec-tion in children who received 50 mg/kg chloral hydrate washigher than in oral midazolam group (87 % vs. 45 %, P <0.001) [18].

In Loewy et al. study, music therapy and chloral hydratewere equally effective for sleep inducing for EEG recording inchildren [19].

In Aksu et al. study, efficacy and safety of dexmedetomidineand midazolam for sedation in EEG recording of children withfebrile seizure were evaluated. Dexmedetomidine groupshowed less change in EEG peak frequency and ampli-tude. But, hypoxia was more frequent in midazolam group[20].

In Mehta et al. study, adequate sedation and completion ofEEG was achieved in 93 % (25 of 27) of children with autisticdisorders who received clonidine which included five patientswho had previously failed to be sedated with chloral hydrate[21].

In other studies, efficacy of drugs in sedation induction fordental procedures was evaluated. Torres-Pérez et al. studyshowed that combination of 0.50 mg/kg midazolam and1.5 mg/kg hydroxyzine or 50 mg/kg chloral hydrate and1.5 mg/kg hydroxyzine were more effective than sole 2mg/kg hydroxyzine in sedation induction for dental proce-dures [22] and in da Costa et al. study, 75 mg/kg of chloralhydrate alone and a combination of 50 mg/kg chloral hydrateand 2 mg/kg plus hydroxyzine were effective in pediatricdental sedation in 62.5 % and 61.5 %, respectively [12] andWilson et al. study showed that, combination of chloral hy-drate, meperidine, and hydroxyzine caused more remarkablequiet and sleeping behaviors than chloral hydrate- hydroxy-zine or oral midazolam. Also, CH + H combination produced

lower mean arterial pressure [23] and in a study in MexicoCity, combination of 70 mg/kg chloral hydrate and 2 mg/kghydroxyzine in comparison to sole 70 mg/kg chloral hydratesignificantly caused decrease in crying and movement in 45–60 min after a rubber dam insertion [24].

In Roach et al. study, efficacy of chloral hydrate, combina-tion of chloral hydrate and diphenhydramine, chloral hydrate -hydroxyzine hydrochloride combination and sole midazolamwas compared in sedation induction for echocardiography. Inchloral hydrate group, children fell asleep most quickly andchloral hydrate and diphenhydramine group experienced themost prolonged sedations [25].

Possible discrepancies justification are differences in age,dose of drug, race, sample size, procedure type, time ofadministration of the drug, usage as a premedication beforeanesthesia or sleep deprivation before drug use in some of theresearches.

In the present study, the three sedation regimens were safeand not life-threatening and severe side effects were witnessedin the three groups. But, in Fávero et al. study, two of 41children who received chloral hydrate in dosage of 50 mg/kghad respiratory depression [26] and in Heistein et al. study,severe adverse events such as apnea happened in 0.3 %,airway obstruction in 1.4 %, hypoxia in 5.9 %, hypercarbiain 6.6 % and hypotension in 0.4 % of kids who receivedchloral hydrate for echocardiography sedation [27].

In the present research, 16.7 % of kids had vomiting.However, vomiting occurred in 0.4 % of kids in a researchin Texas [27], 10 % in a study in Yazd, Iran [28], 11.4 % inGreek research [29] and 30 % in a research in Turkey [30].

In the present study, obtaining sleep in majority of childrenwho were adequately sedated with the three sedation regimensappeared up to 30 min after the administration of the drugs.Therefore, administration of these sedative drugs 30 min be-fore the procedure, may be more effective.

The limitations of the present study are its small samplesize and short duration of follow up. So, it is recommendedthat other studies be done with larger sample sizes, longerfollow up duration and the lowest effective dosages ofantihistamines.

In conclusion, based on findings of the present research, acombination of chloral hydrate in the lowest dose and

Table 3 Comparison of successin EEG recording in both groupsbased on developmental status

The statistical test used: Chi-square test

Success in EEG recording Yes No P value

Data

Developmental status Normal Chloral hydrate (CH) 11 4 0.07CH and promethazine 15 1

CH and hydroxyzine 10 1

Delay Chloral hydrate 10 5 0.23CH and promethazine 14 0CH and hydroxyzine 15 4

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antihistamines is safer and more effective in children EEGsedation. But, the drugs should be administered 30 min beforethe procedure.

Acknowledgments The authors thank Professor Nasrollah Bashardoostfor data analyzing help.

Contributions RF: Writing the manuscript; AA and AS: Gathering thedata; SAK: Editing the manuscript. RFwill act as guarantor for this paper.

Conflict of Interest None.

Role of Funding Source None.

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